Cataract development is a complex process involving a whole range of different causes. The hereditary cataracts in our animal model provide an excellent opportunity to identify changes in gene regulation that will result in the formation of lens opacity. The study of gene expression changes in hereditary cataract of strain 13/N of guinea pigs is particularly important because it provides the only model of nuclear hereditary cataract and because guinea pigs, as humans, are born with their eyes open, when this cataract is already present. A new guinea pig lens crystallin, Zeta-crystallin, discovered in our section by Drs. Huang-Zigler, appears to be absent or sharply reduced in the lens of the cataractous animal. We set up to clone the copy of the mRNA encoding Zeta-crystallin as a first approach to understand which step of the regulation of this gene could be responsible for the development of the cataract. We screened a guinea pig cDNA library with a synthetic oligonucleotide and obtained a positive clone (pTB100) of 1448 base pairs (bp). This clone contains the full zeta-protein coding region of 328 amino acids with a MW of 35,071 daltons; it provided us with the first primary structure of this novel protein. Computer search of the zeta-crystallin sequence in the protein sequence data bank revealed a 33% similarity of this protein with the alcohol dehydrogenase (ADH) protein family. Further analysis of the comparison proved to be statistically significant indicating that zeta-crystallin belongs to the superfamily of the ADHs. The role of this similarity and its significance in lens transparency is under present study.